Janssen Research & Development Briefing Document Arthritis Advisory Committee PLIVENSIA

176 Pages·2012·13.6 MB·English

Janssen Research & Development
Briefing Document
Arthritis Advisory Committee
PLIVENSIA™ (sirukumab)
Status: Approved
Date: 28 June 2017
Prepared by: Janssen Research & Development, LLC
EDMSnumber: EDMS-ERI-141203773
ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
TABLE OF CONTENTS
TABLE OF CONTENTS...............................................................................................................................2
LIST OF IN-TEXT TABLES..........................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................5
LIST OF ABBREVIATIONS AND DEFINITIONS OFTERMS.....................................................................7
1. EXECUTIVE SUMMARY.....................................................................................................................9
2. INTRODUCTION & BACKGROUND................................................................................................16
2.1. Rheumatoid Arthritis: Unmet Medical Need and Current Treatment Paradigm.............................16
2.1.1. IL-6 pathway and IL-6 Receptor Inhibitory Agents in RA...........................................................17
2.2. Sirukumab......................................................................................................................................19
2.2.1. Inhibition of IL-6 by Sirukumab in RA.........................................................................................19
2.2.2. Placement within the RA Treatment Paradigm..........................................................................19
2.3. Formulation Development..............................................................................................................19
2.3.1. Pharmaceutical Form..................................................................................................................20
2.3.2. Device Information......................................................................................................................20
2.4. Proposed Indication and Dosing....................................................................................................21
2.5. Regulatory History..........................................................................................................................21
3. OVERVIEW OF CLINICALDEVELOPMENT PROGRAM...............................................................23
4. SUMMARY OF CINICAL PHARMACOLOGY..................................................................................26
4.1. Pharmacokinetics...........................................................................................................................26
4.2. Drug-Drug Interactions...................................................................................................................26
4.3. Immunogenicity..............................................................................................................................27
4.4. Biomarkers.....................................................................................................................................27
5. SUMMARY OF CLINICAL EFFICACY.............................................................................................29
5.1. Efficacy Endpoints..........................................................................................................................29
5.2. Phase 2 Study................................................................................................................................29
5.2.1. Phase 2 Study Design................................................................................................................29
5.2.2. Phase 2 Efficacy Results: Signs and Symptoms.......................................................................31
5.2.3. Phase 2 Exposure-Response Analysis......................................................................................33
5.2.4. Dose Rationale for Phase 3 Studies...........................................................................................35
5.3. Phase 3 Studies.............................................................................................................................36
5.3.1. Statistical Analyses.....................................................................................................................37
5.4. Phase 3 Studies -Combination Therapy.......................................................................................41
5.4.1. Study ARA3002 (DMARD-IR).....................................................................................................41
5.4.2. ARA3003 (Anti-TNFα-IR)............................................................................................................56
5.5. Efficacy by Baseline Demographic and Disease Characteristics..................................................68
5.5.1. Study ARA3002..........................................................................................................................68
5.5.2. Study ARA3003..........................................................................................................................70
5.6. Phase 3 Studies –Monotherapy....................................................................................................72
5.6.1. Sirukumab Received as Monotherapy in ARA3002 and ARA3003............................................72
5.6.2. Study ARA3005 (Monotherapy)..................................................................................................74
5.7. Efficacy Exposure-Response Analyses.........................................................................................81
5.7.1. Efficacy by Sirukumab Trough Concentration Quartiles.............................................................81
5.7.2. Efficacy Exposure-Response Modeling Analysis.......................................................................83
5.8. Efficacy Conclusions......................................................................................................................84
6. SUMMARY OF CLINICAL SAFETY.................................................................................................86
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
6.1. General Approach to Evaluating and Managing Safety in the Sirukumab Development
Program.........................................................................................................................................86
6.2. Comorbidities and Concomitant Medications of Study Population................................................86
6.3. Safety Database (Exposure)..........................................................................................................87
6.4. Overview of Safety Analysis..........................................................................................................88
6.4.1. Studies ARA3002 and ARA3003................................................................................................88
6.4.2. Study ARA3005..........................................................................................................................90
6.4.3. 120-day Safety Update...............................................................................................................90
6.5. Adverse Events..............................................................................................................................90
6.5.1. Studies 3002 and 3003...............................................................................................................90
6.5.2. Study 3005..................................................................................................................................92
6.6. Serious Adverse Events.................................................................................................................93
6.6.1. Deaths.........................................................................................................................................95
6.7. Adverse Events of Special Interest..............................................................................................100
6.7.1. Infections..................................................................................................................................103
6.7.2. Gastrointestinal Perforations....................................................................................................106
6.7.3. MACE........................................................................................................................................107
6.7.4. Malignancies.............................................................................................................................110
6.7.5. Aminotransferase Abnormalities...............................................................................................112
6.7.6. Neutrophil and Platelet Counts.................................................................................................113
6.7.7. Lipids.........................................................................................................................................114
6.7.8. Injection-site Reactions.............................................................................................................117
6.7.9. Hypersensitivity Reactions........................................................................................................118
6.8. Safety in Subpopulations.............................................................................................................119
6.9. Exposure-Response Analysis for Safety......................................................................................119
6.10. 120-day Safety Update................................................................................................................119
6.11. Sirukumab Safety with Indirect Reference to Other Drugs Used for Rheumatoid Arthritis.........120
6.12. Safety Conclusions......................................................................................................................121
7. DOSE RECOMMENDATION...........................................................................................................124
8. BENEFIT-RISK ASSESSMENT......................................................................................................125
8.1. Overall Assessment.....................................................................................................................125
8.2. Postmarketing Safety Surveillance Plan......................................................................................127
8.3. Benefit-risk Conclusions...............................................................................................................128
9. CONCLUSIONS...............................................................................................................................129
REFERENCES..........................................................................................................................................130
APPENDICES...........................................................................................................................................134
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
LIST OF IN-TEXT TABLES
Table1: Overview of Phase 2 and Phase 3 Studies of Sirukumab in Patients with Active
Rheumatoid Arthritis.................................................................................................................25
Table 2: Overview of Key Efficacy Endpoints (Studies ARA3002 and ARA3003).................................38
Table 3: Summary of Patient Disposition in Study ARA3002 (DMARD-IR)...........................................43
Table 4: Baseline Demographics and Disease Characteristics..............................................................44
Table 5: Primary and Major Secondary Endpoint in ARA3002...............................................................46
Table 6: Inhibition of Progression of Structural Damage; vdH-S Score at Weeks 24 and 52................49
Table 7: Erosion and Joint Space Narrowing Score at Weeks 24 and 52..............................................50
Table 8: HAQ-DI-related Endpoints (Study ARA3002)...........................................................................52
Table 9: SF-36-related Endpoints (Study ARA3002)..............................................................................54
Table 10: FACIT-F-related Endpoints (Study ARA3002)..........................................................................56
Table 11: Summary of Patient Disposition at Week 24 (Study ARA3003)...............................................58
Table 12: Summary of Patient Disposition at Week 52 (Study ARA3003)...............................................58
Table 13: Baseline Demographics and Disease Characteristics (Study ARA3003).................................59
Table 14: Primary and Major Secondary Endpoint (Study ARA3003)......................................................60
Table 15: HAQ-DI-related Endpoints (Study ARA3003)...........................................................................62
Table 16: SF-36-related Endpoints (Study ARA3003)..............................................................................63
Table 17: FACIT-F-related Endpoints (Study 3003).................................................................................65
Table 18: Improvement in Clinical Outcomes; Randomized Patients with Prior Use of Anti-TNFα
Biologics Only and Patients With Prior Use of Other Biologic DMARDs (Study
ARA3003).................................................................................................................................66
Table 19: Improvement in Signs and Symptoms and Physical Function; Randomized Patients
With No Use of DMARDs at Baseline (Studies ARA3002, ARA3003).....................................73
Table 20: Summary of Patient Disposition at Week 24 (Study ARA3005)..............................................76
Table 21: Baseline Demographics and Disease Characteristics (Study ARA3005)................................77
Table 22: Summary of Primary and Key Secondary Endpoints; Full Analysis Set (Study
ARA3005).................................................................................................................................78
Table 23: Medical History and Concomitant Medications: All Patients in ARA3002 and ARA3003.........87
Table 24: Number of Patients by Duration of Exposure Category; Sirukumab Controlled Analysis Set
(Study CNTO136ISS)..................................................................................................................87
Table25: Treatment-emergent AEs in the DMARD-IR and TNFα-Failure Studies..................................91
Table 26: Adverse Reactions Occurring in at Least 2% or More of Patients on Sirukumab 50 mg
and at Least 1% Greater than Placebo.....................................................................................92
Table 27: Summary of Safety in Study ARA3005 (SCS Cut-off)..............................................................93
Table 28: Number of patients with 1or more treatment-emergent SAEs by MedDRA SOC
through 18 weeks of exposure..................................................................................................94
Table 29: AEs of Interest: Incidence per 100 Patient-Years in the DMARD-IR and TNFα-Failure
Studies....................................................................................................................................101
Table 30: Incidence of Infection in Patients with and without ANC<LLN through 18 Weeks of
Exposure in the DMARD-IR and TNFα-Failure Studies.........................................................106
Table 31: Malignancies in Phase 3 sirukumab studies compared with the expected number in
the general population according to the SEER database.......................................................111
Table 32: Aminotransferase Abnormalities in Sirukumab Phase 3 Studies...........................................112
Table33: Number of patients with post-baseline values by maximum toxicity grade for
hematology lab parameters through 18 weeks of exposure...................................................114
Table 34: Shift in LDL and triglycerides from baseline to highest post-baseline value through 18
weeks (Studies 3002 and 3003 pooled).................................................................................116
Table 35: Hypersensitivity reactions excluding injection site reactions..................................................118
Table36: Incidence rate (patient-based per 100 patient years of exposure) of deaths, serious
infections, GI perforations, MACE, malignancy, and hepatobiliary abnormalities during
the sirukumab-controlled period: comparison of data through the SCS and 120-day
safety update cutoff dates.......................................................................................................120
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
LIST OF IN-TEXT FIGURES
Figure 1: Classic and Trans IL-6 Signal Transduction.............................................................................18
Figure 2: Dose-response in Changes of Pharmacodynamic Biomarkers Following 12-week
Treatment with Sirukumab (Study C1377T04 PartB)..............................................................28
Figure 3: Study Design -Study C1377T04 –Part A................................................................................30
Figure 4: Study Design -Study C1377T04 –Part B................................................................................30
Figure 5: Proportion of Patients who Achieved ACR 20/ACR 50 Responses by Visit (Study
C1377T04 Part B).....................................................................................................................32
Figure 6: Mean (SE) Changes from Baseline in DAS28 (CRP) (left panel) or Clinical Disease
Activity Index (CDAI) (right panel) over time (Study C1377T04 Part B)...................................33
Figure 7: Proportion of Patients Who Achieved ACR 20 Response and ACR 50 Response at
Week 24 by Trough Serum Sirukumab Concentration (quartiles) at Week 24; PK
Analysis Set (StudyC1377T04 Part B).....................................................................................34
Figure 8: The Probability of Achieving a Target Value of ≥20% or ≥30% Difference in ACR 20
Response Relative to Placebo at Week 24 by Different Dose Regimens................................35
Figure 9: Study Design -ARA3002 (DMARD-IR)....................................................................................42
Figure 10: Line Plot of the Proportion of Patients Who Achieved an ACR 20 Response by Visit
Through Week 52; (Placebo Controlled Period) (Study ARA3002)..........................................47
Figure 11: Change from Baseline in CDAI Score by Visit through Week 52; Full Analysis Set
(Placebo Controlled Period) (Study ARA3002)........................................................................48
Figure 12: Probability Plot of Change from Baseline in vdH-S at Week 52; Full Analysis Set
(Placebo Controlled Period) for Radiographic Assessment (Study ARA3002)........................51
Figure 13: Change From Baseline in HAQ-DI Score by Visit Through Week 52; Full Analysis Set
(Placebo Controlled Period) (Study ARA3002)........................................................................53
Figure 14: Change in SF-36 Individual Domain Scores at Week 24 (Study ARA3002)...........................55
Figure 15: Study Design -ARA3003 (Anti-TNFα-IR).................................................................................57
Figure 16: Line Plot of the Proportion of Patients Who Achieved an ACR20 Response by Visit
Through Week 24; Placebo Controlled Period) (Study ARA3003)...........................................61
Figure 17: Change in SF-36 Individual Domain Scores at Week 24 (Study ARA3003)............................64
Figure 18: ACR 20 Response at Week 16 by number of prior Anti-TNFs and Biologic Therapies
(ARA3003)................................................................................................................................67
Figure 19: ACR 20 Response at Week 16 by Prior Use of Tocilizumab (Study ARA3003)......................68
Figure 20: Odds Ratios (Sirukumab 50 mg, Placebo; Sirukumab 100 mg, Placebo) for
Comparing the Proportion of Patients Who Achieved ACR 20 Response at Week 16;
Full Analysis Set (Placebo Controlled Period) (Study ARA3002).............................................69
Figure21: Odds Ratios (Sirukumab 50 mg, Placebo; Sirukumab 100 mg, Placebo) for
Comparing the Proportion of Patients Who Achieved ACR 20 Response at Week 16;
Full Analysis Set (Placebo Controlled Period) (Study ARA3003).............................................71
Figure22: Study Design -ARA3005..........................................................................................................75
Figure 23: Change from Baseline in DAS28 (ESR) by Visit through Week 24; Full Analysis Set
(Study ARA3005)......................................................................................................................80
Figure 24: Proportion of Patients Who Achieved ACR 20 or ACR 50 Responses at Week 16 by
Trough Serum Concentration Quartiles at Week 16 (Studies ARA3002 and ARA3003).........82
Figure 25: Observed versus Predicted Week 16 ACR20/ACR50/ACR70 Responses Using
Steady-State Trough Concentration as Exposure Metric (Pooled Data)..................................83
Figure 26: Rate of Serious Adverse Events per 100 PY*..........................................................................95
Figure 27: Rate of Deaths per 100 PY*.....................................................................................................96
Figure 28: Analysis of Death Over Time (SCS Cut-off).............................................................................99
Figure 29: Mortality rates from the sirukumab RCT program and published rates from comparator
RCT programs........................................................................................................................100
Figure 30: Rate of Serious Infections per 100 PY*..................................................................................104
Figure 31: Rate of Gastric Perforations per 100 PY*...............................................................................106
Figure32: Rate of MACE per 100 PY*....................................................................................................108
Figure 33: Indirect comparison of the incidence of MI and stroke on sirukumab and tocilizumab..........109
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
Figure34: Rate of Malignancies per 100 PY*..........................................................................................110
Figure 35: Mean LDL and HDL changes over time with sirukumab........................................................115
Figure 36: Baseline, Pre-and Post-Lipid Lowering Agent (LLA) LDL Cholesterol for Patients
Starting LLAs Post-Baseline (N=205) Sirukumab Combined (50mg q4w and 100mg
q2w)........................................................................................................................................116
Figure 37: Change from baseline in total cholesterol in patients with or without MACE on
sirukumab 50mg (red) and 100 mg (blue).............................................................................117
Figure 38: Rates of mortality and events of interest in the Sirukumab Phase 3 program with a
summary of data from RCTs/ RAdevelopment programs......................................................121
Figure39: Risk Differences for Key Benefits and Key AEI: Studies ARA3002 and ARA3003...............126
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ACR American College of Rheumatology
ADR Adverse drug reactions
AE Adverse event
AEI Adverse events of interest
ALT Alanine aminotransferase
Anti-CCP Anti-cyclic citrullinated peptide
ARDS Acute Respiratory Distress Syndrome
AST Aspartate aminotransferase
AUC Area under the curve
CDAI Clinical Disease Activity Index
CL/F Apparent clearance of drug after extravascular administration
CRP C-reactive protein
DAS28 Disease Activity Index Score 28
DMARD Disease-modifying anti-rheumatic drug
DMARD-IR DMARD-inadequate responder
EE Early escape
EQ-5D EuroQol EQ-5D Descriptive System
E-R Exposure-response
ES Erosion score
ESR Erythrocyte sedimentation rate
EULAR European League Against Rheumatism
FACIT-Fatigue Functional Assessment of Chronic Illness Therapy-Fatigue
FVP Final Vialed Product
GI Gastrointestinal
HAQ-DI Health Assessment Questionnaire-Disability Index
HDL High-density lipoprotein
HCP Health Care Professional
IgG1k ImmunoglobulinG1 k
IL Interleukin
JAK Janus kinase inhibitor
JSN Joint space narrowing
LDL Low-density lipoprotein
LE Late escape
mAb Monoclonal antibody
MACE Major adverse cardiovascular events
MCR Major clinical response
MCS Mental Component Score
MI Myocardial infarction
MTX Methotrexate
NSAID Nonsteroidal anti-inflammatory drug
PCS Physical Component Score
PD Pharmacodynamics
PFS Prefilled syringe
PFS-AI PFS with SmartJect® Autoinjector
PFS-U PFS with UltraSafe Passive®Delivery System
PK Pharmacokinetics
PMR Polymyalgia rheumatica
q2w every 2 weeks
q4w every 4 weeks
QOL Health-related quality of life
RA Rheumatoid arthritis
SAE Serious adverse event
SCS Summary of clinical safety
SDAI Simplified Disease Activity Index
SF-36 36-item Short Form health survey
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
SINF Serious infections
SOC System Organ Class
T1/2 Terminal half-life
TB Tuberculosis
TNFα Tumor necrosis factor alpha
TNFα-IR TNFα-inadequate responder
ULN Upper limit of normal
vdH-S Van der Heijde-modified Sharp
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
1. EXECUTIVE SUMMARY
This document provides background information on the clinical development program of
sirukumab for the treatment of rheumatoid arthritis (RA) and outlines the benefit-risk profile
supporting its use in this patient population.
Sirukumab (PLIVENSA™) is a human anti-IL-6 immunoglobulin G1 kappa (IgG1)
monoclonal antibody (mAb) that binds specifically with high affinity to the cytokine IL-6,
preventing IL-6-mediated signalling. Inhibition of the IL-6 pathway in RA has been clinically
validated by tocilizumab (ACTEMRA), a treatment targeting the IL-6 pathway by binding the
IL-6 receptor (IL-6R). Recently, another IL-6R antagonist, sarilumab (KEVZARA), was
approved by the Food and Drug Administration (FDA). Sirukumab would be the first inhibitor of
IL-6 to be approved by the FDA for the treatment of RA.
The proposed indication for sirukumab is as follows:
PLIVENSIA, an interleukin-6 (IL-6) inhibitor, is indicated for the treatment of adult
patients with moderately to severely active rheumatoid arthritis (RA) who have had an
inadequate response or are intolerant to one or more disease modifying anti-rheumatic
drugs (DMARDs). PLIVENSIA may be used as monotherapy or in combination with
nonbiologic DMARDs, including methotrexate (MTX).
Disease and Unmet Medical Need
Rheumatoid arthritis is a common, chronic, life-long, autoimmune disease affecting
approximately 1.3 million people in the US. Although it primarily affects joints and is a leading
cause of disability when left untreated, RA also has extra-articular manifestations with systemic
effects including cardiovascular morbidity, fatigue, and depression. A variety of treatment
options including nonsteroidal anti-inflammatory drugs (NSAID), non-biologic disease
modifying antirheumatic drugs (DMARD), or biologic DMARDs are available. It is well
recognized that proinflammatory cytokines, including tumor necrosis factor alpha (TNFα),
interleukin-1 (IL-1), and interleukin-6 (IL-6), play significant roles in the pathogenesis of the
disease, contributing to both joint inflammation and comorbidities. In the last 2 decades, new
treatments targeting these pathways have provided additional treatment options for patients.
However, RA patients are still not adequately managed and often are left with few remaining
therapeutic options due to loss of response to available agents, and poor compliance due to
inconvenient dosing. Many patients still fail to achieve control of their disease and sustained
disease remission is uncommon. Due to the duration and chronic nature of RA, patients can
expect to require treatment for up to 40 years over their lifetime. Individual patient factors and
comorbidities influence treatment selection and use; however, how patients will respond to a
given therapy remains unpredictable. Patients commonly discontinue medication due to
inadequate response, loss of response, adverse reactions, or other issues such as poor compliance
resulting from frequent or inconvenient dosing.52,59Patients try multiple drugs within a class or
will cycle to new therapies in a different class. The relatively high likelihood that a patient will
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Status: Approved, Date: 28 June 2017
PLIVENSIA™ (sirukumab)
Rheumatoid arthritis Briefing Document
stop responding to any particular therapy means that many patients will exhaust available
treatment options during the course of their disease. Thus, there still remains a considerable
unmet need in this chronic disease that requires lifelong therapy. In addition to the currently
approved biologic therapies, new safe, effective and convenient therapies are required to improve
the signs and symptoms of the disease, slow down joint structural damage, and address the
systemic manifestations of RA to improve the overall quality of life for patients.
Sirukumab Clinical Development Program
A large global clinical development program evaluated a diverse patient population
representative of current clinical practice, including difficult-to-treat patients who continue to
have active disease in spite of previous use of biologics.
This program was designed to meet the needs of patients and to comply with global regulatory
authorities.
 A Phase 2 study, C1377T04, was designed as a placebo-controlled, proof-of-concept and
dose-finding study in MTX-IR patients withactive RA.
 Two global pivotal Phase 3 studies were designed to evaluate sirukumab 50 mg q4w and
100mg q2w given subcutaneously in combination with background DMARDs:
 ARA3002: the first pivotal study (2-year duration) with a one year placebo-control arm
in patients who were inadequate responders to single or combination disease modifying
antirheumatic drug (DMARD) therapy that included methotrexate (MTX) or
sulfasalazine (SSZ). Patients could also have received a biologic DMARD prior to
study entry.
This study included x-ray evaluation of joint damage.
 ARA3003: the second pivotal study (1-year duration) with a 6-month placebo-control
arm in patients who were inadequate responders to treatment with 1 or more anti-tumor
necrosis factor alpha (TNFα) agents or intolerant to 2 or more anti-TNFα agents.
Patients were also allowed to have previous exposure to other biologics including anti-
IL-6 agents.
All eligible patients from ARA3002 and ARA3003 could continue treatment in the
ARA3004 long-term extension (LTE) study for a maximum of up to 5 years.
 Efficacy of sirukumab monotherapy was investigatedby:
 a subgroup analysis of patients treated with sirukumab without concomitant DMARDs
in studies ARA3002 and ARA3003, and a 1-year active comparator study, ARA3005,
in biologic-naïve patients with active RA who were intolerant to MTX.
Summary of Major Efficacy Findings
In the 2 pivotal Phase 3 placebo-controlled studies, ARA3002 (DMARD-IR study) and
ARA3003 (anti-TNFα-IR study), benefits were demonstrated across a difficult-to-treat patient
population representing the full spectrum of moderately to severely active adult RA, ie, patients
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Status: Approved, Date: 28 June 2017